title: Synthesis of 4'-Ethynyl-2'-deoxy-4'-thioribonucleosides and Discovery of a Highly Potent and Less Toxic NRTI.
abstract: The synthesis of 4'-ethynyl-2'-deoxy-4'-thioribonucleosides was carried out utilizing an electrophilic glycosidation in which 4-ethynyl-4-thiofuranoid glycal16served as a glycosyl donor. Electrophilic glycosidation between16and the silylated nucleobases (N4-acetylcytosine,N6-benzoyladenine andN2-acetyl-O6-diphenylcarbamoylguanine) was carried out in the presence ofN-iodosuccinimide (NIS) leading to the exclusive formation of the desired β-anomers29, 33and36. Anti-HIV studies demonstrated that these 4'-thio nucleosides were less cytotoxic to T-lymphocyte (i.e. MT-4 cells) than the corresponding 4'-ethynyl derivatives of 2'-deoxycytidine (44), 2'-deoxyadenosine (45) and 2'-deoxyguanosine (46). Comparison of the selectivity indices (SI) was made between 4'-thionucleosides (32, 41and43) and the corresponding 4'-oxygen analogues44-46by using the reported CC50and EC50values. In the case of cytosine and adenine nucleosides, comparable SI values were obtained:32(545) and45(458);41(>230) and45(1,630). In contrast, 4'-ethynyl-2'-deoxy-4'-thioguanosine43was found to possess a SI value of >18,200, which is twenty times better than that of46(933).
authors.affiliation: School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Haraguchi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Shimada
authors.forename: Keiogo
authors.initials: K
authors.lastname: Kimura
authors.forename: Genta
authors.initials: G
authors.lastname: Akutsu
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Tanaka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Abe
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hamasaki
authors.forename: Masanori
authors.initials: M
authors.lastname: Baba
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Gullen
authors.forename: Ginger E
authors.initials: GE
authors.lastname: Dutschman
authors.forename: Yung-Chi
authors.initials: YC
authors.lastname: Cheng
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
keywords: 4’-thionucleosides; anti-HIV-1 activity; electrophilic glycosidation; glycal; nucleoside reverse transcriptase inhibitors